Techniques for nerve stimulation

ABSTRACT

Apparatus is provided for applying current to a nerve, including a housing, adapted to be placed in a vicinity of the nerve, and at least one cathode and at least one anode, fixed to the housing. The apparatus further includes two or more passive electrodes, fixed to the housing, and a conducting element, which electrically couples the passive electrodes to one another. Other embodiments are also described.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present patent application claims the benefit of U.S. ProvisionalPatent Application 60/628,391, filed Nov. 15, 2004, which is assigned tothe assignee of the present application and is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates generally to electrical stimulation oftissue, and specifically to methods and devices for regulating thestimulation of nerves.

BACKGROUND OF THE INVENTION

In the body, axons are grouped together for most of their lengths innerve bundles. In a single bundle, many different axons travel together,branching only near their target organs. Important properties of naturalaxonal activity include that: (a) each axon can fire independently ofits neighbors in the bundle, and (b) each axon conveys action potentialsin only one direction, either afferently (towards the brain) orefferently (towards its target organ). These two properties, however,are not properties of the axons themselves. The axons are only activecables emanating from neurons which can trigger action potentials inthem. Since each axon can be connected to a different neuron, they canfire independently. Also, because the axons are connected to a neurononly on one side, they only convey action potentials away from theneuron.

When axons are activated artificially by simple stimulation of a nervebundle, both of these properties of natural axonal activity are lost:entire regions of the bundle are activated simultaneously, and the axonsfire in both directions at once, since the action potential is nottriggered at only one of the ends of the axons. The loss of theseproperties causes the effect of artificial stimulation to be lessnatural, and may result in side effects, because axons in the bundle inaddition to the target axon are indiscriminately activated. To overcomethese shortcomings of simple stimulation, two stimulation techniqueshave been developed: selective stimulation and unidirectionalstimulation.

Selective electrical stimulation of nerve fibers is the activation ofsmall fibers in a nerve bundle without the activation of the largefibers. This is advantageous, for example, when the target organ isinnervated only by small fibers. In addition, stimulation of largefibers can cause unwanted side effects (see, for example, Rijkhoff etal. (1994) and Jones JF et al., cited hereinbelow). Often, in additionto selective stimulation, it is also advantageous to stimulateunidirectionally such that only organs at one end of the nerve receivesignals.

As defined by Rattay, in the article, “Analysis of models forextracellular fiber stimulation,” IEEE Transactions on BiomedicalEngineering, Vol. 36, no. 2, p. 676, 1989, which is incorporated hereinby reference, the activation function (AF) of an unmyelinated axon isthe second spatial derivative of the electric potential along an axon.In the region where the activation function is positive, the axondepolarizes, and in the region where the activation function isnegative, the axon hyperpolarizes. If the activation function issufficiently positive, then the depolarization will cause the axon togenerate an action potential; similarly, if the activation function issufficiently negative, then local blocking of action potentialstransmission occurs. The activation function depends on the currentapplied, as well as the geometry of the electrodes and of the axon.

For a given electrode geometry, the equation governing the electricalpotential is:

∇(σ∇U)=4πj,

where U is the potential, σ is the conductance tensor specifying theconductance of the various materials (electrode housing, axon,intracellular fluid, etc.), and j is a scalar function representing thecurrent source density specifying the locations of current injection.The activation function is found by solving this partial differentialequation for U. If an unmyelinated axon is defined to lie in the zdirection, then the activation function is:

${A\; F} = {\frac{\partial^{2}U}{\partial z^{2}}.}$

In a simple, illustrative example of a point electrode located adistance d from the axis of an axon in a uniformly-conducting mediumwith conductance a, the two equations above are solvable analytically,to yield:

${{A\; F} = {\frac{I_{el}}{4{\pi\sigma}} \cdot \frac{{2z^{2}} - d^{2}}{\left( {z^{2} + d^{2}} \right)^{2.5}}}},$

where I_(el) is the electrode current. It is seen that when a and d areheld constant, and for a constant positive I_(el) (to correspond toanodal current), the minimum value of the activation function isnegative, and is attained at z=0, i.e., at the point on the nerveclosest to the source of the anodal current. Thus, the most negativepoint on the activation function corresponds to the place on a nervewhere hyperpolarization is maximized, namely at the point on the nerveclosest to the anode.

Additionally, this equation predicts positive “lobes” for the activationfunction on either side of z=0, these positive lobes peaking in theirvalues at a distance which is dependent on each of the other parametersin the equation. The positive values of the activation functioncorrespond to areas of depolarization, a phenomenon typically associatedwith cathodic current, not anodal current. However, it has been shownthat excess anodal current does indeed cause the generation of actionpotentials adjacent to the point on a nerve corresponding to z=0, andthis phenomenon is therefore called the “virtual cathode effect.” (Ananalogous, but reverse phenomenon, the “virtual anode effect” existsresponsive to excess cathodic stimulation.)

The Rattay article also describes techniques for calculating theactivation function for nerves containing myelinated axons. Theactivation function in this case varies as a function of the diameter ofthe axon in question. Thus, the activation function calculated for a 1micron diameter myelinated axon is different from the activationfunction calculated for a 10 micron diameter axon.

U.S. Pat. No. 6,684,105 to Cohen et al., which is assigned to theassignee of the present application and is incorporated herein byreference, describes apparatus comprising an electrode device adapted tobe coupled to longitudinal nervous tissue of a subject, and a controlunit adapted to drive the electrode device to apply to the nervoustissue a current which is capable of inducing action potentials thatpropagate in the nervous tissue in a first direction, so as to treat acondition. The control unit is further adapted to suppress actionpotentials from propagating in the nervous tissue in a second directionopposite to the first direction.

U.S. Pat. No. 6,907,295 to Gross et al., which is assigned to theassignee of the present application and is incorporated herein byreference, describes apparatus for applying current to a nerve. Acathode is adapted to be placed in a vicinity of a cathodic longitudinalsite of the nerve and to apply a cathodic current to the nerve. Aprimary inhibiting anode is adapted to be placed in a vicinity of aprimary anodal longitudinal site of the nerve and to apply a primaryanodal current to the nerve. A secondary inhibiting anode is adapted tobe placed in a vicinity of a secondary anodal longitudinal site of thenerve and to apply a secondary anodal current to the nerve, thesecondary anodal longitudinal site being closer to the primary anodallongitudinal site than to the cathodic longitudinal site.

A number of patents and articles describe methods and devices forstimulating nerves to achieve a desired effect. Often these techniquesinclude a design for an electrode or electrode cuff.

U.S. Pat. Nos. 4,608,985 to Crish et al. and 4,649,936 to Ungar et al.,which are incorporated herein by reference, describe electrode cuffs forselectively blocking orthodromic action potentials passing along a nervetrunk, in a manner intended to avoid causing nerve damage.

PCT Patent Publication WO 01/10375 to Felsen et al., which isincorporated herein by reference, describes apparatus for modifying theelectrical behavior of nervous tissue. Electrical energy is applied withan electrode to a nerve in order to selectively inhibit propagation ofan action potential.

U.S. Pat. No. 5,755,750 to Petruska et al., which is incorporated hereinby reference, describes techniques for selectively blocking differentsize fibers of a nerve by applying direct electric current between ananode and a cathode that is larger than the anode.

U.S. Pat. No. 5,824,027 Hoffer et al., which is incorporated herein byreference, describes a nerve cuff having one or more sets of electrodesfor selectively recording electrical activity in a nerve or forselectively stimulating regions of the nerve. Each set of electrodes islocated in a longitudinally-extending chamber between a pair oflongitudinal ridges which project into the bore of the nerve cuff. Theridges are electrically insulating and serve to improve the selectivityof the nerve cuff. The ridges seal against an outer surface of the nervewithout penetrating the nerve. In an embodiment, circumferential endsealing ridges extend around the bore at each end of the longitudinalridges, and are described as enhancing the electrical and/or fluidisolation between different ones of the longitudinally-extendingchambers.

U.S. Pat. No. 4,628,942 to Sweeney et al., which is incorporated hereinby reference, describes an annular electrode cuff positioned around anerve trunk for imposing electrical signals on to the nerve trunk forthe purpose of generating unidirectionally propagated action potentials.The electrode cuff includes an annular cathode having a circular passagetherethrough of a first diameter. An annular anode has a larger circularpassage therethrough of a second diameter, which second diameter isabout 1.2 to 3.0 times the first diameter. A non-conductive sheathextends around the anode, cathode, and nerve trunk. The anode andcathode are placed asymmetrically to one side of the non-conductivesheath.

U.S. Pat. No. 5,423,872 to Cigaina, which is incorporated herein byreference, describes a process for treating obesity and syndromesrelated to motor disorders of the stomach of a patient. The processconsists of artificially altering, by means of sequential electricalpulses and for preset periods of time, the natural gastric motility ofthe patient to prevent emptying or to slow down gastric transit. The'872 patent describes an electrocatheter adapted to be coupled to aportion of the stomach. A portion of the electrocatheter has a roughsurface for producing a fibrous reaction of the gastric serosa, in orderto contribute to the firmness of the anchoring.

U.S. Pat. No. 4,573,481 to Bullara, which is incorporated herein byreference, describes an implantable helical electrode assembly,configured to fit around a nerve, for electrically triggering ormeasuring an action potential or for blocking conduction in nervetissue. A tissue-contacting surface of each electrode is roughened toincrease the electrode surface area.

The following patents, which are incorporated herein by reference, maybe of interest:

-   U.S. Pat. No. 6,230,061 to Hartung-   U.S. Pat. No. 5,282,468 to Klepinski-   U.S. Pat. No. 4,535,785 to van den Honert et al.-   U.S. Pat. No. 5,215,086 to Terry et al.-   U.S. Pat. No. 6,341,236 to Osorio et al.-   U.S. Pat. No. 5,487,756 to Kallesoe et al.-   U.S. Pat. No. 5,634,462 to Tyler et al.-   U.S. Pat. No. 6,456,866 to Tyler et al.-   U.S. Pat. No. 4,602,624 to Naples et al.-   U.S. Pat. No. 6,600,956 to Maschino et al.-   U.S. Pat. No. 5,199,430 to Fang et al.

The following articles, which are incorporated herein by reference, maybe of interest:

-   Ungar IJ et al., “Generation of unidirectionally propagating action    potentials using a monopolar electrode cuff,” Annals of Biomedical    Engineering, 14:437-450 (1986)-   Sweeney JD et al., “An asymmetric two electrode cuff for generation    of unidirectionally propagated action potentials,” IEEE Transactions    on Biomedical Engineering, vol. BME-33(6) (1986)-   Sweeney JD et al., “A nerve cuff technique for selective excitation    of peripheral nerve trunk regions,” IEEE Transactions on Biomedical    Engineering, 37(7) (1990)-   Naples GG et al., “A spiral nerve cuff electrode for peripheral    nerve stimulation,” by IEEE Transactions on Biomedical Engineering,    35(11) (1988)-   van den Honert C et al., “Generation of unidirectionally propagated    action potentials in a peripheral nerve by brief stimuli,” Science,    206:1311-1312 (1979)-   van den Honert C et al., “A technique for collision block of    peripheral nerve: Single stimulus analysis,” MP-11, IEEE Trans.    Biomed. Eng. 28:373-378 (1981)-   van den Honert C et al., “A technique for collision block of    peripheral nerve: Frequency dependence,” MP-12, IEEE Trans. Biomed.    Eng. 28:379-382 (1981)-   Rijkhoff N J et al., “Acute animal studies on the use of anodal    block to reduce urethral resistance in sacral root stimulation,”    IEEE Transactions on Rehabilitation Engineering, 2(2):92-99 (1994)-   Mushahwar VK et al., “Muscle recruitment through electrical    stimulation of the lumbo-sacral spinal cord,” IEEE Trans Rehabil    Eng, 8(1):22-9 (2000)-   Deurloo KE et al., “Transverse tripolar stimulation of peripheral    nerve: a modelling study of spatial selectivity,” Med Biol Eng    Comput, 36(1):66-74 (1998)-   Tarver WB et al., “Clinical experience with a helical bipolar    stimulating lead,” Pace, Vol. 15, October, Part II (1992)-   Hoffer JA et al., “How to use nerve cuffs to stimulate, record or    modulate neural activity,” in Neural Prostheses for Restoration of    Sensory and Motor Function, Chapin JK et al. (Eds.), CRC Press (1st    edition, 2000)-   Jones JF et al., “Heart rate responses to selective stimulation of    cardiac vagal C fibres in anaesthetized cats, rats and rabbits,” J    Physiol 489(Pt 1):203-14 (1995)-   Evans M S et al., “Intraoperative human vagus nerve compound action    potentials,” Acta Neurol Scand 110:232-238 (2004)

In physiological muscle contraction, nerve fibers are recruited in theorder of increasing size, from smaller-diameter fibers to progressivelylarger-diameter fibers. In contrast, artificial electrical stimulationof nerves using standard techniques recruits fibers in a larger- tosmaller-diameter order, because larger-diameter fibers have a lowerexcitation threshold. This unnatural recruitment order causes musclefatigue and poor force gradation. Techniques have been explored to mimicthe natural order of recruitment when performing artificial stimulationof nerves to stimulate muscles.

Fitzpatrick et al., in “A nerve cuff design for the selective activationand blocking of myelinated nerve fibers,” Ann. Conf. of the IEEE Eng. inMedicine and Biology Soc, 13(2), 906 (1991), which is incorporatedherein by reference, describe a tripolar electrode used for musclecontrol. The electrode includes a central cathode flanked on itsopposite sides by two anodes. The central cathode generates actionpotentials in the motor nerve fiber by cathodic stimulation. One of theanodes produces a complete anodal block in one direction so that theaction potential produced by the cathode is unidirectional. The otheranode produces a selective anodal block to permit passage of the actionpotential in the opposite direction through selected motor nerve fibersto produce the desired muscle stimulation or suppression.

The following articles, which are incorporated herein by reference, maybe of interest:

-   Rijkhoff N J et al., “Orderly recruitment of motoneurons in an acute    rabbit model,” Ann. Conf. of the IEEE Eng., Medicine and Biology    Soc., 20(5):2564 (1998)-   Rijkhoff N J et al., “Selective stimulation of small diameter nerve    fibers in a mixed bundle,” Proceedings of the Annual Project Meeting    Sensations/Neuros and Mid-Term Review Meeting on the TMR-Network    Neuros, Apr. 21-23, 1999, pp. 20-21 (1999)-   Baratta R et al., “Orderly stimulation of skeletal muscle motor    units with tripolar nerve cuff electrode,” IEEE Transactions on    Biomedical Engineering, 36(8):836-43 (1989)

The following articles, which are incorporated herein by reference,describe techniques using cuff electrodes to selectively exciteperipheral nerve fibers distant from an electrode without exciting nervefibers close to the electrode:

-   Grill WM et al., “Inversion of the current-distance relationship by    transient depolarization,” IEEE Trans Biomed Eng, 44(1):1-9 (1997)-   Goodall EV et al., “Position-selective activation of peripheral    nerve fibers with a cuff electrode,” IEEE Trans Biomed Eng,    43(8):851-6 (1996)-   Veraart C et al., “Selective control of muscle activation with a    multipolar nerve cuff electrode,” IEEE Trans Biomed Eng,    40(7):640-53 (1993)

One method used for selective stimulation is based on the observationthat the stimulation/block threshold of fibers is inversely proportionalto their radius. Thus, to stimulate only small fibers, all fibers arestimulated using a large cathodic current, and the large fibers are thenblocked using a smaller anodal current, the net effect being actionpotential propagation in the small fibers only. To achieveunidirectional stimulation, one uses larger anodic currents on one side,thus blocking all fibers on that side. Because of the intrinsicphysiological timescales of the ion channels in the axon, to block anaction potential one uses a long pulse of approximately 1 millisecond.This long pulse may degrade stimulation efficiency. By comparison, anaction potential can be triggered with pulses as short as approximately10 microseconds.

A method for selective stimulation is described in Lertmanorat Z et al.,“A novel electrode array for diameter-dependent control of axonalexcitability: a simulation study,” IEEE Transactions on BiomedicalEngineering 51(7):1242-1250 (2004), which is incorporated herein byreference. The described Electrode Array Selective Stimulation (EASS)method relies on the structure of myelinated fibers and employselectrode arrays. The myelinated fibers are surrounded by a sheath ofmyelin, which functions as an isolator. In this sheath there are gaps atregular intervals, called nodes of Ranvier. The gap distance is roughlyproportional to the radius of the axon. Ion channels are present only atthese gaps.

The principle of EASS is that if an electric field is produced which isperiodic along a nerve, and the period matches the gap distance of anaxon with a certain diameter, then the axon essentially “sees” aconstant electric field, so that no stimulation/block occurs. Axons ofdifferent gap-distances see a varying field and are thusstimulated/blocked. The variation in the electric field that an axon“sees” depends on the ratio between its gap distance and the fieldperiod. The variation also depends on the radial distance (depth) fromthe electrode to the axon. As the axon gets further away from theelectrode, the field becomes less varying since the cathodic and anodalfields tend to cancel each other. The inventors of the present patentapplication estimate that the fields vary in a substantial manner up toa radial distance of about one period of the field. It should be notedthat at all distances, the field has the same periodicity. Therefore,axons with a nodal gap distance which matches the field period will notbe activated at any depth, but other axons may not be activated becausethe field becomes too weak.

Since the gap distance is proportional to the axon radius, by selectinga period for the field to change, a range of axon radii can be selectedwhich are substantially not affected by the electric field. Setting theperiod of the field to be the gap distance of large fibers ensures thatlarge fibers will not be affected by the stimulation. An advantage ofthis method for selective stimulation is that stimulus duration can beshort; no blocking is needed since the large fibers are simply notactivated.

An EASS electrode can be made by placing an alternating series of anodeand cathodes along the axon, spaced a gap width apart. The cathodes andanodes can be ring shaped to give better field uniformity inside thenerve.

The main shortcoming of this method is that while it enables selectivestimulation with short pulses, it does not provide unidirectionalstimulation.

SUMMARY OF THE INVENTION

In some embodiments of the present invention, an electrode assembly forapplying current to a nerve comprises at least one cathode, at least oneanode, and two or more passive electrodes, which are fixed within ahousing. The electrode assembly comprises a conducting element,typically a wire, which electrically couples the passive electrodes toone another. A “passive electrode,” as used in the present applicationincluding the claims, is an electrode that is electrically“device-coupled” to neither (a) any circuitry that is electricallydevice-coupled to the at least one cathode or the at least one anode,nor (b) an energy source. “Device-coupled” means coupled, directly orindirectly, by components of a device, and excludes coupling via tissueof a subject. (It is noted that the passive electrodes may be passivebecause of a software-controlled setting of the electrode assembly, andthat the software may intermittently change the setting such that theseelectrodes are not passive.) To “passively electrically couple,” as usedin the present application including the claims, means to couple usingat least one passive electrode and no non-passive electrodes. Thepassive electrodes and conducting element create an electrical path forcurrent that would otherwise leak outside the electrode assembly andtravel around the outside of the housing through tissue of the subject.

For some applications, the at least one cathode and at least one anodeare positioned within the housing longitudinally between the two or morepassive electrodes. Alternatively, at least one of the passiveelectrodes is positioned between the at least one cathode and the atleast one anode. For some applications, the electrode assembly isconfigured to apply unidirectional stimulation to the nerve.Alternatively or additionally, the electrode assembly is configured toselectively stimulate fibers of the nerve having certain diameters.

In some embodiments of the present invention, an electrode assembly forapplying current to a nerve comprises two cathodes and at least oneanode, which are fixed within a housing such that no anodes arepositioned between the two cathodes. (If any anode is positioned betweenthe two cathodes, then in at least one mode of operation, this anodeapplies no more than a trivial amount of anodal current to the nerve.)Typically, a distance between the two cathodes is equal to at least aradius of the nerve, e.g., at least 1.5 times the radius of the nerve.This electrode configuration creates a combined cathode having anactivation function a peak of which has a magnitude less that of theanode, which results in unidirectional stimulation of the nerve in thedirection of the cathodes. Typically, this electrode configuration alsocreates a virtual anode on the side of the cathodes opposite that of theanode, which results in selective fiber stimulation of fibers of thenerve having relatively small diameters. For some applications, theelectrode assembly additionally comprises two or more passive electrodescoupled to one another, as described above, positioned such that thecathodes and the at least one anode are between the passive electrodes.

In some embodiments of the present invention, an electrode assembly forapplying current to a nerve comprises a housing, which is placed in avicinity of the nerve, one or more electrodes, fixed to the housing, andtwo longitudinally-elongated end insulating elements, fixed to thehousing such that all of the electrodes are longitudinally between theinsulating elements. Each of the end insulating elements has a length ofat least 2 mm, such as at least 3 mm, or at least 4 mm. This elongationof the end insulating elements tends to lengthen the electrical patharound the outside of the electrode assembly through tissue of thesubject, thereby reducing the current that leaks from the assembly andflows through this path.

There is therefore provided, in accordance with an embodiment of thepresent invention, apparatus for applying current to a nerve, including:

a housing, adapted to be placed in a vicinity of the nerve;

at least one cathode and at least one anode, fixed to the housing;

two or more passive electrodes, fixed to the housing; and

a conducting element, which electrically couples the passive electrodesto one another.

In an embodiment, the two or more passive electrodes include exactly twopassive electrodes.

In an embodiment, the at least one cathode and the at least one anodeare fixed longitudinally between the two or more passive electrodes.Alternatively, at least one of the passive electrodes is fixedlongitudinally between the at least one cathode and the at least oneanode.

For some applications, the at least one anode includes one or moreanodes which are configured to apply to the nerve an inhibiting currentcapable of inhibiting cathode-induced action potentials traveling in anon-therapeutic direction in the nerve. For some applications, the atleast one cathode includes one or more cathodes which are configured toapply to the nerve a stimulating current, which is capable of inducingaction potentials in a first set and a second set of nerve fibers of thenerve, and the at least one anode includes one or more anodes that areconfigured to apply to the nerve an inhibiting current, which is capableof inhibiting the induced action potentials in the second set of nervefibers, the nerve fibers in the second set having generally largerdiameters than the nerve fibers in the first set.

For some applications, the electrodes include ring electrodes. For someapplications, the conducting element includes at least one passiveelement that impedes passage of current through the conducting element.For some applications, the housing includes one or more insulatingelements that separate one or more of the at least one cathode, the atleast one anode, and the passive electrodes, the insulating elementspositioned closer to the nerve than are the at least one cathode, the atleast one anode, and the passive electrodes.

There is also provided, in accordance with an embodiment of the presentinvention, apparatus for applying current to a nerve of a subject,including:

a housing, adapted to be placed in a vicinity of the nerve;

at least one cathode and at least one anode, fixed to the housing;

a passive electrode, fixed to the housing; and

a conducting element, which is electrically coupled to the passiveelectrode and extends to a remote location in a body of the subject at adistance of at least 1 cm from the housing.

There is further provided, in accordance with an embodiment of thepresent invention, apparatus for applying current to a nerve having aradius, including:

a housing, adapted to be placed in a vicinity of the nerve; and

two or more cathodes and one or more anodes, fixed to the housing suchthat no anodes are positioned longitudinally between the two or morecathodes.

In an embodiment, the apparatus includes two or more passive electrodes,fixed to the housing, such that the cathodes and the anodes arelongitudinally between the passive electrodes; and a conducting element,which electrically couples the passive electrodes to one another.

For some applications, the two or more cathodes and the one or moreanodes include ring electrodes. For some applications, the housingincludes one or more insulating elements that separate one or more ofthe cathodes and the anodes, the insulating elements positioned closerto the nerve than are the cathodes and the anodes.

In an embodiment, the cathodes and anodes are fixed to the housing suchthat no cathodes are positioned longitudinally between the one or moreanodes.

In an embodiment, the two or more cathodes are fixed to the housing atrespective cathodic longitudinal locations, and are configured to applyto the nerve a stimulating current, which is capable of inducing actionpotentials in a first set and a second set of nerve fibers of the nerve;the one or more anodes are fixed to the housing at respective anodallocations, such that no cathodes are positioned longitudinally betweenthe one or more anodes; the cathodes are configured to produce a virtualanode effect at a virtual anodal longitudinal site of the nerve, whichis capable of inhibiting the induced action potentials in the second setof nerve fibers, the nerve fibers in the second set having generallylarger diameters than the nerve fibers in the first set; and thecathodic locations are between (a) the anodal locations and (b) thevirtual anodal site.

In an embodiment, the two or more cathodes are fixed to the housing atrespective cathodic locations; the one or more anodes include a singleanode, fixed to the housing at an anodal location; the anode isconfigured to produce a virtual cathode effect at a virtual cathodiclongitudinal site of the nerve, which is incapable of generating actionpotentials in the nerve; and the anodal location is between (a) thecathodic locations and (b) the virtual cathodic site. Alternatively, theanode is configured to produce the virtual cathode effect at the virtualcathodic longitudinal site which does not generate action potentials inmore than 10% of axons in the nerve.

In an embodiment, the cathodes are positioned such that a closestdistance between two of the two or more cathodes is equal to at leastthe radius of the nerve, such as equal to at least 1.5 times the radiusof the nerve.

In an embodiment, the cathodes are configured to apply respectivecathodic currents to the nerve; the anodes are configured to applyrespective anodal currents to the nerve; and for any given depth withinthe nerve, for a myelinated axon within the nerve of diameter less than10 microns, the cathodic currents define, in combination, for the depth,a cathodic activation function having a maximum depolarizing amplitude,and the anodal currents define, in combination, for the depth, an anodalactivation function having a maximum hyperpolarizing amplitude greaterthan the maximum depolarizing amplitude. For some applications, for a 1micron diameter myelinated axon within the nerve, the maximumhyperpolarizing amplitude is greater than or equal to 110% of themaximum depolarizing amplitude.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus for applying current to a nerve, including:

a housing, adapted to be placed in a vicinity of the nerve;

one or more cathodes, fixed to the housing, and configured to applyrespective cathodic currents to the nerve; and

one or more anodes, fixed to the housing, and configured to applyrespective anodal currents to the nerve,

wherein, for any given depth within the nerve, for a myelinated axonwithin the nerve of diameter less than 10 microns, the cathodic currentsdefine, in combination, for the depth, a cathodic activation functionhaving a maximum depolarizing amplitude, and the anodal currents define,in combination, for the depth, an anodal activation function having amaximum hyperpolarizing amplitude greater than the maximum depolarizingamplitude.

For some applications, for a 1 micron diameter myelinated axon withinthe nerve, the maximum hyperpolarizing amplitude is greater than orequal to 110% of the maximum depolarizing amplitude.

In an embodiment, the one or more cathodes include two or more cathodes,fixed to the housing such that no anodes are positioned longitudinallybetween the two or more cathodes.

In an embodiment, the cathodes and anodes are fixed to the housing suchthat no cathodes are positioned longitudinally between the one or moreanodes.

In an embodiment, the one or more cathodes are fixed to the housing atrespective cathodic locations; the one or more anodes include a singleanode, fixed to the housing at an anodal location; the anode isconfigured to produce a virtual cathode effect at a virtual cathodiclongitudinal site of the nerve, which is incapable of generating actionpotentials in the nerve; and the anodal location is between (a) thecathodic locations and (b) the virtual cathodic site. Alternatively, theanode is configured to produce the virtual cathode effect at the virtualcathodic longitudinal site which does not generate action potentials inmore than 10% of axons of the nerve.

There is yet further provided, in accordance with an embodiment of thepresent invention, apparatus for applying current to a nerve, including:

a housing, adapted to be placed in a vicinity of the nerve;

one or more electrodes, fixed to the housing; and

two elongated end insulating elements, fixed to the housing such thatall of the electrodes are longitudinally between the insulatingelements, and adapted to be disposed with respect to the nerve such thateach of the end insulating elements has a length in a direction parallelwith the nerve of at least 2 mm.

For some applications, each of the end insulating elements has a maximumthickness along at least 75% of its length of less than 0.5 mm. For someapplications, the end insulating elements are adapted to be positionedcloser to the nerve than are the electrodes. For some applications, thehousing includes one or more internal insulating elements that separateone or more of the electrodes, the internal insulating elements beingadapted to be positioned closer to the nerve than the electrodes.

For some applications, the length of each of the end insulating elementsis at least 3 mm, or at least 4 mm.

There is also provided, in accordance with an embodiment of the presentinvention, a method for applying current to a nerve, including: applyingat least one cathodic current and at least one anodal current to thenerve; and passively electrically coupling at least two longitudinalsites of the nerve to one another.

There is further provided, in accordance with an embodiment of thepresent invention, a method for applying current to a nerve of asubject, including:

applying at least one cathodic current and at least one anodal currentto the nerve; and

passively electrically coupling at least one site of the nerve to aremote location in a body of the subject at a distance of at least 1 cmfrom the nerve.

There is still further provided, in accordance with an embodiment of thepresent invention, a method for applying current to a nerve having aradius, including:

applying two or more cathodic currents to the nerve at respectivecathodic longitudinal sites; and

applying one or more anodal currents to the nerve at respective anodallongitudinal sites,

without applying anodal current to the nerve at any site longitudinallybetween the two or more cathodic longitudinal sites.

There is yet further provided, in accordance with an embodiment of thepresent invention, method for applying current to a nerve, including:

applying one or more cathodic currents to the nerve; and

applying one or more anodal currents to the nerve,

wherein, for any given depth within the nerve, for a myelinated axonwithin the nerve of diameter less than 10 microns, the cathodic currentsdefine, in combination, for the depth, a cathodic activation functionhaving a maximum depolarizing amplitude, and the anodal currents define,in combination, for the depth, an anodal activation function having amaximum hyperpolarizing amplitude greater than the maximum depolarizingamplitude.

There is also provided, in accordance with an embodiment of the presentinvention, a method for applying current to a nerve, including:

applying one or more currents to the nerve at respective longitudinalcurrent-application sites of the nerve; and

applying electrical insulation to the nerve at two longitudinalinsulation sites of the nerve, wherein all of the current-applicationsites are longitudinally between the two insulation sites, and each ofthe insulation sites has a length in a direction parallel with the nerveof at least 2 mm.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method, including:

applying, to a stimulation site of a nerve, a spatially-periodicstimulating field, configured to induce, in small fibers of the nerve,action potentials that propagate from the stimulation site towards atarget site and away from the target site; and

applying, to an inhibition site of the nerve, a spatially-periodicnon-stimulating field, configured to partially depolarize at theinhibition site the small fibers of the nerve, without initiating actionpotentials therein,

the partial depolarization of the small fibers being sufficient toinhibit the action potentials propagating away from the target site fromcontinuing to propagate beyond the inhibition site,

the stimulation site being between the target site and the inhibitionsite.

The present invention will be more fully understood from the followingdetailed description of embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-3 are schematic, cross-sectional illustration of electrodeassemblies for applying current to a nerve, in accordance withrespective embodiments of the present invention;

FIGS. 4 and 5 are graphs modeling calculated activation functions whencurrent is applied using an electrode assembly similar to that of FIG.3, in accordance with an embodiment of the present invention;

FIG. 6 is a schematic, cross-sectional illustration of another electrodeassembly for applying current to a nerve, in accordance with anembodiment of the present invention;

FIG. 7 is a schematic, cross-sectional illustration of an electrodeassembly for applying Electrode Array Selective Stimulation (EASS) to anerve, in accordance with an embodiment of the present invention; and

FIG. 8 is a schematic illustration of a selective stimulation EASSsystem, in accordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF EMBODIMENTS

FIG. 1 is a schematic, cross-sectional illustration of an electrodeassembly 20 for applying current to a nerve 30, in accordance with anembodiment of the present invention. It is noted that although thevarious electrode assemblies shown in the figures and described hereingenerally contain cylindrical configurations of their elements, othergeometrical configurations, such as non-rotationally symmetricconfigurations, are also suitable for applying the principles of thepresent invention. In particular, a housing of the electrode assemblies(and the electrodes themselves) may form a complete circle around thenerve, or it may define an arc between approximately 0 and 90 degrees,between 90 and 180 degrees, between 180 and 350 degrees, or between 350and 359 degrees around the nerve. For some applications, the electrodeassemblies shown in the figures and described herein comprise electrodesthat form rings around the nerve, and an insulating, elastic cuff thatsurrounds the electrodes.

Electrode assembly 20 comprises at least one active, i.e., stimulatingand/or sensing, electrode 38, such as at least one cathode 41 and atleast one anode 42. Each of these electrodes is fixed within a housing22 of the electrode assembly. Active electrodes 38 are coupled to animplantable or external control unit 40 by leads 42 and 44. For someapplications, active electrode configurations and/or stimulationtechniques are used which are described in one or more of the patentapplications incorporated by reference hereinbelow.

Electrode assembly 20 further comprises two or more passive electrodes50, fixed within housing 22, and a conducting element 52, typically awire, which electrically couples the passive electrodes to one another.The electrode assembly is configured such that the passive electrodesare electrically device-coupled, as defined hereinabove, to neither (a)any circuitry that is electrically device-coupled to the at least onecathode 41 or the at least one anode 42, nor (b) an energy source.Passive electrodes 50 and conducting element 52 create an electricalpath for current that would otherwise leak outside electrode assembly 30and travel around the outside of the housing through tissue of thesubject.

For some applications, the active electrodes are positioned withinhousing 22 longitudinally between the two or more passive electrodes 50(as shown in FIG. 1). Alternatively, at least one of the passiveelectrodes is positioned between the at least one cathode and the atleast one anode (configuration not shown).

Internal insulating elements 24, which are either part of the body ofthe housing or affixed thereto, are typically placed so as to separatethe electrodes, and to guide current from one of the electrodes towardsthe nerve prior to being taken up by another one of the electrodes.Typically (as shown), the insulating elements are closer to nerve 30than are the electrodes. Alternatively (not shown), insulating elements24 are generally flush with the faces of the electrodes. The electrodeassembly typically further comprises one or more end insulating elements26, which extend along nerve in order to electrically isolate a portionof the nerve within housing 22 from a portion of the nerve outside theelectrode assembly. The end insulating elements help direct any currentthat leaks from the active electrodes through the electrical pathcreated by the passive electrodes and the conducting element. For someapplications, conducting element 52 comprises at least one passiveelement 54, such as a resistor, capacitor, and/or inductor.

For some applications, the electrode assembly is configured toselectively stimulate fibers of the nerve having certain diameters, suchas by using techniques described in one or more of the patentapplications incorporated by reference hereinbelow. For example, controlunit 40 may drive cathode 41 to apply to nerve 30 a stimulating current,which is capable of inducing action potentials in a first set and asecond set of nerve fibers of the nerve, and drive anode 42 to apply tothe nerve an inhibiting current, which is capable of inhibiting theinduced action potentials traveling in the second set of nerve fibers,the nerve fibers in the second set having generally larger diametersthan the nerve fibers in the first set.

For some applications, the electrode assembly is configured to applyunidirectional stimulation to the nerve, such as by using techniquesdescribed in one or more of the patent applications incorporated byreference hereinbelow. For example, control unit 40 may drive anode 42to apply an inhibiting current capable of inhibiting device-inducedaction potentials traveling in a non-therapeutic direction in nerve 30.For some applications, electrode assembly 20 comprises primary andsecondary anodes, the primary anode located between the secondary anodeand the cathode. The secondary anode is typically adapted to apply acurrent with an amplitude less than about one half an amplitude of acurrent applied by the primary anode.

In an embodiment of the present invention, electrode device 20 comprisesone or more passive electrodes 50 which are not electricallydevice-coupled to one another. For some applications, the electrodedevice comprises exactly one passive electrode 50. A separate conductingelement, typically a wire, is coupled to each passive electrode at afirst end of the conducting element. The second end of the conductingelement terminates at a relatively-remote location in the body of thesubject that is at a distance of at least 1 cm, e.g., at least 2 or 3cm, from electrode device 20. The remote location in the body thusserves as a ground for the passive electrode. For some applications, anelectrode is coupled to the remote end of the conducting element, so asto increase electrical contact with tissue at the remote location.

Reference is made to FIG. 2, which is a schematic, cross-sectionalillustration of an electrode assembly 120 for applying current to nerve30, in accordance with an embodiment of the present invention. Electrodeassembly 120 comprises two cathodes 141 a and 141 b and at least oneanode 142, which are fixed within a housing 122 such that no anodes arepositioned between the two cathodes. Cathodes 141 a and 141 b areelectrically coupled to one another, and are coupled to an implantableor external control unit 140 by a lead 142. Anode 142 is coupled tocontrol unit 140 by a lead 144. Typically, a closest distance D betweenthe two cathodes (i.e., the distance between the respective cathodes'edges that are closest to one another) is equal to at least a radius Rof nerve 30, e.g., at least 1.5 times the radius of the nerve.

As described in detail hereinbelow with reference to FIGS. 4 and 5, thiselectrode configuration creates a combined cathode having an activationfunction a peak of which has a magnitude less than that of anode 142,which results in a stimulation that results in unidirectionalpropagation of action potentials in the nerve, in the direction goingfrom anode 142 towards the cathodes. Typically, this electrodeconfiguration also creates a virtual anode on the side of the cathodesopposite that of the anode, which results in selective fiber stimulationof fibers of the nerve having relatively small diameters.

Typically, electrode assembly 120 does not comprise any anodes on theside of the cathodes opposite anode 142 (i.e., the left side in thefigures). However, for some applications, in which the virtual anodecreated on the side of the cathodes opposite the anode is not strongenough to create sufficient selective fiber stimulation, electrodeassembly 120 comprises a second anode on the side of cathodes 141 a and141 b opposite anode 142. A portion of the anodal current is driventhrough this anode in order to strengthen the blocking oflarger-diameter fibers, thereby increasing the selection of thestimulation of small-diameter fibers. Typically, only a relatively smallportion of the anodal current is driven through this second anode, inorder to leave sufficient current for anode 142 to block all (or a verylarge portion of) action potentials generated by cathodes 141 a and 141b (i.e., in order to preserve unidirectional stimulation).

For some applications, the electrode configuration of electrode assembly120 is combined with electrode configurations and/or stimulationtechniques described in one or more of the patent applicationsincorporated by reference hereinbelow.

Internal insulating elements 124, which are either part of the body ofthe housing or affixed thereto, are typically placed so as to separatethe electrodes, and to guide current from one of the electrodes towardsthe nerve prior to being taken up by another one of the electrodes.Typically (as shown), the insulating elements are closer to nerve 30than are the electrodes. Alternatively (not shown), insulating elements124 are generally flush with the faces of the electrodes. The electrodeassembly typically further comprises one or more end insulating elements126, which extend along nerve 30 in order to electrically isolate aportion of the nerve within housing 122 from a portion of the nerveoutside the electrode assembly.

Reference is made to FIG. 3, which is a schematic, cross-sectionalillustration of an electrode assembly 220 for applying current to nerve30, in accordance with an embodiment of the present invention. Electrodeassembly 220 is the same as electrode assembly 120, describedhereinabove with reference to FIG. 2, except that electrode assembly 220further comprises, on the ends thereof, two passive electrodes 50 a and50 b and conducting element 52, as described hereinabove with referenceto FIG. 1. Typically, a closest distance between anode 142 and passiveelectrode 50 b is between about 0.7 mm and about 1 mm. Conductingelement 52 optionally comprises passive element 54, as describedhereinabove with reference to FIG. 1.

Reference is now made to FIGS. 4 and 5, which are graphs modelingcalculated activation functions 300 and 302, respectively, of myelinatednerve fibers having a diameter of 1 micrometer, over a portion of thelength of nerve 30, when current is applied using an electrode assemblysimilar to that shown in FIG. 3, in accordance with an embodiment of thepresent invention. For the purposes of modeling these activationfunctions, (a) cathodes 141 a and 141 b are placed at longitudinal siteson the nerve labeled z=−2 mm and z=2 mm, respectively, (b) anode 142 isplaced at a longitudinal site z=4.1 mm, and (c) passive electrodes 50 aand 50 b are placed at longitudinal sites z=−4.1 mm and z=5.5 mm,respectively. All of the electrodes are placed at a radius of R=2.5 mmfrom the axis of nerve 30, which has a radius of 1.35 mm. Activationfunctions 300 (FIGS. 4) and 302 (FIG. 5) are modeled at radii R=1.2 fromthe axis of nerve 30 (near the surface of the nerve) and R=(i.e., at theaxis of the nerve), respectively.

Activation function 300 (FIG. 4) has two depolarization peaks 304 and306, at approximately z=−2.5 and z=2.5, corresponding to thelongitudinal positions of the two cathodes. In activation function 302(FIG. 5), these two depolarization peaks have partially combined into asingle, wide depolarization peak 308. Each of activation functions 300and 302 has a hyperpolarization peak 310 at approximately z=4,corresponding to the longitudinal position of the anode. For a givenfiber diameter (in this case, 1 micrometer), at all depths within thenerve, the amplitude of the hyperpolarization peak is greater than theamplitude of greatest depolarization peak, such as at least 10% or 20%greater. As a result, the hyperpolarization peak blocks propagation ofsubstantially all cathode-induced action potentials traveling in thenerve from the cathode in the direction of the anode (i.e., to the rightin the figures).

Each of activation functions 300 and 302 has a second, smallerhyperpolarization peak 312 at between about z=−4 and about z=−5,approximately corresponding to the longitudinal position of passiveelectrode 50 a. This “virtual anode” effect, which is caused by cathodes141 a and 141 b and passive electrode 50 a, blocks propagation of almostall cathode-induced action potentials traveling in large- andmedium-diameter fibers, but not those in small-diameter fibers,resulting in selective small-diameter fiber activation in the directionfrom cathode 141 a to passive electrode 50 a (i.e., to the left in thefigures). It is noted that in the absence of passive electrode 50 a (inthe embodiment described with reference to FIG. 2), the two-cathodeconfiguration still results in the virtual anode effect between aboutz=−4 and about z=−5. Current flows through tissue around the outside ofthe electrode assembly, rather than between the passive electrodes viaconducting element 52.

Activation functions 300 and 302 additionally have a second, smallerdepolarization peak 314 at between about z=6 and z=8, approximatelycorresponding to the longitudinal position of passive electrode 50 b.This “virtual cathode” effect, which is caused by anode 142 and passiveelectrode 50 b, does not generate action potentials in more than 10% ofaxons of nerve 30 (or does not generate action potentials in any axonsof nerve 30) because of the virtual cathode's relatively low amplitude,and its vicinity to strong hyperpolarization peak 310.

It is noted that if cathodes 141 a and 141 b are positioned at a closestdistance D less than radius R of nerve 30 (FIG. 2), the cathodes beginto behave as a single cathode, generating a depolarization peak having agreater amplitude than those in activation functions 300 and 302. As aresult, the amplitude of hyperpolarization peak 310 is no longer greaterthan the amplitude of the greatest depolarization peak at all nervefiber diameters. The stimulation is thus not unidirectional at all nervefiber diameters.

Reference is made to FIG. 6, which is a schematic, cross-sectionalillustration of an electrode assembly 320 for applying current to nerve30, in accordance with an embodiment of the present invention. Electrodeassembly 320 comprises one or more electrodes, such as at least onecathode 341 and at least one anode 342, which are fixed within a housing322. Electrode assembly 320 further comprises two elongated endinsulating elements 326, which are either part of the body of thehousing or affixed thereto. The end insulating elements extend alongnerve 30 in order to electrically isolate a portion of the nerve withinhousing 322 from a portion of the nerve and other tissue outside theelectrode assembly. Each of the end insulating elements has a length Lof at least 2 mm, such as at least 3 mm, or at least 4 mm. Thiselongation of the end insulating elements tends to lengthen theelectrical path around the outside of the electrode assembly throughtissue of the subject, thereby reducing the current that leaks from theassembly and flows through this path.

For some applications, the insulating elements have a thickness T alongat least 75% of their length of less than about 0.5 mm. For someapplications, at least one internal insulating element 324, which iseither part of the body of the housing or affixed thereto, is placed soas to separate the electrodes, and to guide current from one of theelectrodes towards the nerve prior to being taken up by another one ofthe electrodes.

Reference is made to FIG. 7, which is a schematic, cross-sectionalillustration of an electrode assembly 420 for applying Electrode ArraySelective Stimulation (EASS) to nerve 30, in accordance with anembodiment of the present invention. EASS assembly 420 comprisesalternating anodes 442 and cathodes 441. Typically, five anodes 442 andfour cathodes 441 are adequate to create a periodic electric field alonga sufficiently long length of nerve. A control unit 440 is configured todrive the electrodes of EASS assembly 420 to apply a spatially-periodicfield to nerve 30 that is configured to target fibers of a selecteddiameter, as described in the Background of the Invention sectionhereinabove.

Internal insulating elements 424, which are either part of the body ofthe housing or affixed thereto, are typically placed so as to separatethe electrodes, and to guide current from one of the electrodes towardsthe nerve prior to being taken up by another one of the electrodes.Typically (as shown), the insulating elements are closer to nerve 30than are the electrodes. Alternatively (not shown), insulating elements424 are generally flush with the faces of the electrodes. The electrodeassembly typically further comprises one or more end insulating elements426, which extend along nerve 30 in order to electrically isolate aportion of the nerve within the housing from a portion of the nerveoutside the electrode assembly.

Reference is made to FIG. 8, which is a schematic illustration of aselective stimulation EASS system 500, in accordance with an embodimentof the present invention. EASS system 500 comprises two EASS assemblies420 (FIG. 7), and a control unit 540 electrically coupled to bothassemblies. The control unit, at any given time, configures one of theassemblies to function as an activating EASS assembly 510, and the otherto function as a non-stimulating EASS assembly 512. (Alternatively, oneof the assemblies is permanently configured to function as activatingEASS assembly 510, and the other is permanently configured to functionas non-stimulating EASS assembly 512.)

Control unit 540 drives activating EASS assembly 510 to apply aspatially-periodic stimulating field to nerve 30, and configures thefield to induce, in small fibers of the nerve, action potentials thatpropagate towards a target site (in the direction indicated by an arrow546) and away from the target site. The control unit also drivesnon-stimulating EASS assembly 512 to apply a spatially-periodicnon-stimulating field, and to configure the field to partiallydepolarize the small fibers of the nerve, without initiating actionpotentials therein or in larger fibers of the nerve. The partialdepolarization of the small fibers is sufficient to inhibit the actionpotentials generated by activating EASS assembly 510 in a directionopposite the target site from continuing to propagate beyond theinhibition site of non-stimulating EASS assembly 512. As a result,unidirectional small-diameter fiber stimulation is achieved towards thetarget site (i.e., in the direction indicated by arrow 546). Both thestimulating and non-stimulating fields are typically applied using shortpulses, e.g., pulses having a duration of between about and about 100microseconds. The amplitude of the stimulating pulses is typicallybetween about 0.5 and about 15 mA, depending on the number of fibers tobe activated, and the amplitude of the non-stimulating pulses istypically between about 0.1 and about 5 mA, depending on the number offibers to be blocked. During each application of stimulation, thenon-stimulating field is typically applied slightly before applicationof the stimulating field, e.g., between about 500 and about 0microseconds earlier.

Application of the non-stimulating field by non-stimulating EASSassembly 512 causes a partial depolarization of the target axons, whichcauses some of the ion channels in the axons to begin their gatingcycles. However, the non-stimulating field is configured so to minimizethe likelihood of causing depolarization sufficient to trigger an actionpotential. As a result of the partial depolarization, a portion of theion channels enter their refractory periods. When a stimulating field issubsequently applied, these channels cannot begin the gating cycle. As aresult, the number of channels available is insufficient to trigger anaction potential. The fibers are therefore unable to transmit actionpotentials.

Typically, the field applied by non-stimulating EASS assembly 512 isconfigured to partially depolarize only small fibers, by using the EASSselective-fiber-diameter stimulation techniques described hereinabove.

It is noted that the triggering thresholds of axons vary based on theaxons' diameters. Thus, a pulse of a magnitude sufficient to partiallydepolarize small fibers may trigger action potentials in large-diameterfibers. Therefore, without the use of the EASS partial depolarizationtechniques described herein, application of a conventional depolarizingpulse causes undesired complete depolarization (i.e., action potentialgeneration) in large-diameter fibers, in addition to the desired partialdepolarization of small-diameter fibers.

Alternatively, for some applications, applying the non-stimulating fieldcomprises applying a non-EASS non-stimulating pulse, at a strengthsufficient to cause partial depolarization of target axons, butinsufficient to trigger an action potential.

For some applications, EASS system 500 comprises a single long EASSelectrode assembly. The non-stimulating pulse is applied by a portion(e.g., about half) of the electrode assembly on the side thereof furtherfrom the target direction. The stimulating pulse is applied by theremaining portion (e.g., the other half) of the electrode assembly onthe side thereof closer to the target direction. Alternatively, thestimulating pulse is applied by the entire electrode assembly, or anysufficiently long portion thereof. Use of the entire electrode devicefor applying the stimulating pulse generally results in a more periodicfield having a lower current density.

In an embodiment of the present invention, EASS system 500 is configuredto perform unidirectional stimulation of a human vagus nerve. The systemis configured to selectively activate only A-delta fibers, while notactivating A fibers. In the human vagus nerve, the conduction velocityof A and A-delta fibers is about 20 m/sec and about 8 m/sec,respectively (see Evans M S et al., cited hereinabove). These velocitiesimply nodal gaps of 0.5 mm and 0.2 mm, respectively. The inter-electrodedistance D between the respective centers of the electrodes (FIG. 7) isthus typically about 0.5 mm, which enables excitation of A-delta fibersup to a depth from the nerve surface of approximately 0.5 mm. For ahuman vagus nerve with a diameter of about 2.5 mm, these fibersconstitute about 75% of the fibers in the bundle, assuming that they areuniformly scattered throughout the bundle. The length of a single EASSelectrode with five anodes and four cathodes (as shown in FIG. 7) istypically less than about 1 cm, and two such electrodes are readilyplaced side-by-side on a human vagus nerve.

The scope of the present invention includes embodiments described in thefollowing applications, which are assigned to the assignee of thepresent application and are incorporated herein by reference. In anembodiment, techniques and apparatus described in one or more of thefollowing applications are combined with techniques and apparatusdescribed herein:

-   -   U.S. Provisional Patent Application 60/383,157 to Ayal et al.,        filed May 23, 2002, entitled, “Inverse recruitment for autonomic        nerve systems,”    -   International Patent Application PCT/IL02/00068 to Cohen et al.,        filed Jan. 23, 2002, entitled, “Treatment of disorders by        unidirectional nerve stimulation,” and U.S. patent application        Ser. No. 10/488,334, in the national stage thereof,    -   U.S. patent application Ser. No. 09/944,913 to Cohen and Gross,        filed Aug. 31, 2001, entitled, “Treatment of disorders by        unidirectional nerve stimulation,” which issued as U.S. Pat. No.        6,684,105,    -   U.S. patent application Ser. No. 09/824,682 to Cohen and Ayal,        filed Apr. 4, 2001, entitled “Method and apparatus for selective        control of nerve fibers,”    -   U.S. patent application Ser. No. 10/205,475 to Gross et al.,        filed Jul. 24, 2002, entitled, “Selective nerve fiber        stimulation for treating heart conditions,”    -   U.S. patent application Ser. No. 10/205,474 to Gross et al.,        filed Jul. 24, 2002, entitled, “Electrode assembly for nerve        control,” which issued as U.S. Pat. No. 6,907,295,    -   International Patent Application PCT/IL03/00431 to Ayal et al.,        filed May 23, 2003, entitled, “Selective nerve fiber stimulation        for treating heart conditions,”    -   International Patent Application PCT/IL03/00430 to Ayal et al.,        filed May 23, 2003, entitled, “Electrode assembly for nerve        control,” and U.S. patent application Ser. No. 10/529,149, in        the national stage thereof,    -   U.S. patent application Ser. No. 10/719,659 to Ben David et al.,        filed Nov. 20, 2003, entitled, “Selective nerve fiber        stimulation for treating heart conditions,”    -   U.S. patent application Ser. No. 11/022,011 to Cohen et al.,        filed Dec. 22, 2004, entitled, “Construction of electrode        assembly for nerve control,” and    -   U.S. patent application Ser. No. 11/234,877 to Ben-David et al.,        filed Sep. 22, 2005, entitled, “Selective nerve fiber        stimulation.”

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description.

1-9. (canceled)
 10. Apparatus for applying current to a nerve of asubject, comprising: a control unit; a housing, adapted to be placed ina vicinity of the nerve; at least one cathode and at least one anode,fixed to the housing, and electrically device-coupled to the controlunit; a passive electrode, fixed to the housing; and a conductingelement, which is electrically coupled to the passive electrode andextends to a remote location in a body of the subject at a distance ofat least 1 cm from the housing wherein the control unit and the passiveelectrode are configured such that the passive electrode is electricallydevice-coupled to neither (a) any circuitry that is electricallydevice-coupled to the at least one cathode or the at least one anode,nor (b) an energy source. 11-28. (canceled)
 29. Apparatus for applyingcurrent to a nerve, comprising: a housing, adapted to be placed aroundthe nerve, so as to define a longitudinal axis; one or more electrodes,fixed to the housing; and two elongated end insulating elements, fixedto the housing such that all of the electrodes are longitudinallybetween the end insulating elements, and such that each of the endinsulating elements has a length in a direction parallel with thelongitudinal axis nerve of at least 2 mm.
 30. The apparatus according toclaim 29, wherein each of the end insulating elements has a maximumthickness along at least 75% of its length of less than 0.5 mm.
 31. Theapparatus according to claim 29, wherein the end insulating elements areadapted to be positioned closer to the longitudinal axis than are theelectrodes.
 32. The apparatus according to claim 29, wherein the housingcomprises one or more internal insulating elements that separate one ormore of the electrodes, the internal insulating elements being adaptedto be positioned closer to the longitudinal axis than the electrodes.33. The apparatus according to claim 29, wherein the length of each ofthe end insulating elements is at least 3 mm.
 34. The apparatusaccording to claim 33, wherein the length of each of the end insulatingelements is at least 4 mm. 35-41. (canceled)
 42. A method for applyingcurrent to a nerve of a subject, comprising: applying at least onecathodic current and at least one anodal current to the nerve; andpassively electrically coupling at least one site of the nerve to aremote location in a body of the subject at a distance of at least 1 cmfrom the nerve. 43-58. (canceled)
 59. A method for applying current to anerve, comprising: applying one or more currents to the nerve atrespective longitudinal current-application sites of the nerve; andapplying electrical insulation to the nerve at two longitudinalinsulation sites of the nerve, wherein all of the current-applicationsites are longitudinally between the two insulation sites, and each ofthe insulation sites has a length in a direction parallel with the nerveof at least 2 mm.